The main objectives for this study are: (a) To test the hypothesis that estrogens augment the response to fluoxetine, a selective serotonin reuptake inhibitor (SSRI), in premenopausal women who have failed to show a full response after six weeks of treatment with fluoxetine alone. (b) To evaluate the effects of estrogen supplementation on cognition in depressed premenopausal women who have failed to respond fully to treatment with fluoxetine alone for six weeks. (c) To determine the effect of fluoxetine and estrogen administration on lymphocyte glucocorticoid receptors. Eligible subjects will be recruited from clinic populations and by advertisement followed by phone screening. 120 subjects are sought across 3 sites (Stanford University, University of Michigan, and Cornell University); 40 are sought at the Stanford site. The subjects will be divided into two groups, group A and group B. Protocol for groups A and B: All 40 subjects will be assessed at baseline for depression and for cognitive performance. Screening tests: history and physical exam, serum beta-hCG, TSH, Chem 20, urine drug screen; and baseline blood tests: glucocorticoid receptors, estrogen, and cortisol will be done. The total amount of blood required for these tests is less than 100 cc. A physical examination and medical history will also be part of the screening process. Eligible subjects will be put on 20 mg/day fluoxetine for four weeks and be assessed for depression at two week intervals (see table for tests to be used). After four weeks, the dosage of fluoxetine may be increased to 40 mg/day if a subject's mood is not significantly improved. After six weeks, a final evaluation will be done (including a depression assessment, cognitive tests, cortisol, estrogen, and glucocorticoid receptors. Subjects who exhibit less than a 50% reduction in Hamilton Depression Scale score (compared to baseline) and a Hamilton score of at least 12 will be eligible for the second phase of the study. Gynecological clearance will be obtained before subjects may participate in the second (estrogen) phase of the study. The gynecologist giving clearance must have given the subject a pelvic exam and PAP smear within the past year and found her to be normal. If the subject has had an exam in the past year, a gynecologist's letter of clearance for the study will suffice. If the subject does not produce a letter of clearance, an exam will be provided for her. In the second phase of the study, patients will be randomized to placebo or estradiol 10 mg/day and will continue on fluoxetine for an additional four weeks. Mood assessment will be done at week eight. At week ten, subjects will be finished with the study and will have mood assessments, cognitive tests, glucocorticoid receptor assays and estrogen and cortisol levels. A telephone follow-up at week fourteen will assess depression status four weeks after completion of the second phase of the study. Protocol for Group B In addition to the study described above, Group B (20 subjects) will undergo an [18F]-fluoro-deoxyglucose (FDG) PET scan with accompanying MRI scan, as well as a metyrapone challenge to assess HPA axis activity. PET Scan: FDG PET protocol that will be followed is entitled "Cerebral glucose metabolism in mood disorders and healthy volunteers" and has been approved by Human Subjects. The principal investigator is Terence Ketter, M.D.. Metyrapone Challenge: The metyrapone challenge will take place prior to beginning fluoxetine treatment. The challenge will be carried out at the GCRC in Stanford Hospital. An intravenous catheter for blood drawing is inserted at 3:45 PM. 750 mg metyrapone is administered orally at 4 PM. ACTH and cortisol levels are drawn every 30 minutes between 4 PM and 10 PM. Subjects eat dinner between 5:30 and 6:15 PM. A repeat dose of metyrapone will be given at 7:30 PM. Patients may spend the night at the GCRC if they wish, but this is not required. Approximately 78 cc of blood will be required for the metyrapone challenge. As of 2/10/99, 6 patients (2 in group A and 4 in group B) have been enrolled into this study at Stanford University. Of these patients, 2 have entered the second phase of the study. We continue to seek interested and eligible subjects.